tbuckley/cabot-search huggingface dataset:
PB1843: ACUTE MYELOID LEUKEMIA WITH PHILADELPHIA CHROMOSOME: EXPERIENCE OF SFAX HEMATOLOGY DEPARTMENT
Authors: N. Siala, L. Khelifa, I. Frikha, F. Kallel, H. Sennana, S. Menif, N. Ben abdeljalil, S. Laddeb, Y. Fakhfekh, I. Ben Amor, O. Kassar, S. Hadiji, M. Charfi, T. Ben othmen, M. Medhaffar, M. Elloumi
Journal: HemaSphere (2022)

Background: Acute myeloid leukemia with Philadelphia chromosome (AML Ph+) is recently been listed in the 2016 revised World Health Organization (WHO) classification of myeloid malignancies as a provisional entity. Aims: A rare entity whose treatment is not yet established. we are studying the characteristics of a series of patients with AML Phi+. Methods: It’s a retrospective study over 15 years (2005-2019) which includes patients with AML Phi+, diagnosed and treated in the clinical hematology department of Hedi Chaker Sfax Hospital / TUNISIA. We are interested in studying the clinical and biological characteristics, the different treatments received and overall survival (OS). Known patients followed for Chronic Myeloid Leukemia (CML) and who are transformed into blast phase are excluded. Results: Among 264 cases of newly diagnosed AML, we collected 5 cases of AML Phi+ (1.8%). The average age was 43 years (range: 34 to 54). Sex-ratio was 1.5. On initial examination, splenomegaly was found in all cases. WBC counts less than 10 G/l, from 10 to 100 G/L and more than 100 G/L were observed respectively in 20, 40 and 40% of cases. Myelemia was found in 4 cases (80%) and basophilia greater than 2% was noted in 3 cases (60%). Cytogenetic study showed the presence of a t (9.22) in all cases, which was isolated in 1 case. The BCR-ABL transcript was of the p190 type in 2 cases and p210 in 2 cases, while the molecular study was not done in the remaining case. Four patients were treated with tyrosine kinase inhibitor (TKI) alone with the achievement of complete remission (CR) in 3/4 of the cases while one patient was treated with the combination TKI and chemotherapy with good evolution. Allograft was not done for all patients, in 2 cases for the absence of an HLA compatible siblings donor. The median follows up was 108 months. Relapse was observed in 2 patients with CR2 in both cases. The five years OS was 80%. Summary/Conclusion: Phi+ AML in our series is higher than that reported in the literature (1.8 vs <1%) this could be explained by the underestimation of the total number of AML in our country because some patients with AML (>55 years old) are not treated. The major question that arises in front of each phi+ AML is: is it a newly phi+ AML or a CML diagnosed at a blast phase? Previous abnormalities of the blood count, significant myelemia, blood basophilia >2% and the presence of associated cytogenetic abnormality tends towards CML diagnosed at a blast phase while the BCR-ABL transcript type is non-specific. By referring to these data, we can deduce that for our series most probably it is a newly phi+ AML in 2 cases. The major problem posed in the different series is the absence of standardized treatment due to the rarity of the pathology.
P1505: USING ARTIFICIAL INTELLIGENCE NEURAL NETWORKS TO OBTAIN AUTOMATED LIVER IRON CONCENTRATION MEASUREMENTS USING MAGNETIC RESONANCE IMAGING – A MULTI-SCANNER VALIDATION STUDY
Authors: T. St Pierre, Y. Aydinok, A. El-Beshlawy, S. Bayraktaroglu, A. Ibrahim, M. Hamdy, W. Pang, S. Khorshid, S. Bangma, M. House
Journal: HemaSphere (2022)

Background: Because of the limitations of serum ferritin and liver biopsy for measuring liver iron concentration (LIC), magnetic resonance imaging (MRI) methods have been developed. Reliable use of these methods requires extra training of radiologists or outsourcing of the data analysis. While the cost of outsourcing data analysis is acceptable to many patients or providers in high income countries, the majority of hemoglobinopathy patients reside in low-income countries. Therefore, automated LIC measurements using artificial intelligence (AI) or deep-learning-assessed (DLA) algorithms could provide the solution for globally affordable and reliable patient monitoring of LIC. Aims: The aim of this study was to evaluate the performance of an automated deep-learning-based medical device (DLA R2-MRI) for measuring liver iron concentration (LIC) from MRI using an independent multi-scanner dataset. Methods: The tested device was assessed prospectively on 1395 eligible consecutive MRI datasets from 66 different scanners submitted for expert manual analysis using spin-density projection assisted (SDPA) R2-MRI (the reference standard) between August 2017 and July 2020. The aetiologies for iron overload reported by the radiologists submitting the image data were thalassaemias (498), hereditary haemochromatosis (161), sickle cell disease (145), MDS (11), other (309), unknown (271). The bias and limits of agreement between the automated and manual measurements of LIC were assessed. In addition, diagnostic performance was assessed using sensitivity and specificity. Results: The distribution of LIC values measured by the reference method was 0-1.8 mg Fe/g (17.6%), 1.8-3.2 mg Fe/g (16.7%), 3.2 – 5.0 mg Fe/g (14.8%), 5.0 – 7.0 mg Fe/g (11.4%), 7.0-15.0 mg Fe/g (18.6%), >15.0 mg Fe/g (21.0%). Automated LIC results from the DLA R2-MRI had geometric mean ratios to manual results from SDPA R2-MRI of 0.98 (95% CI 0.94 – 1.01) below 3 mg Fe/g dry tissue and 0.93 (95% CI 0.92 – 0.95) above 3mg Fe/g dry tissue were recorded. The sensitivities and specificities of the automated system for predicting LIC values above clinically relevant thresholds of 3.0, 3.2, 5.0, 7.0, and 15.0 mg Fe/g dry tissue were > 90%. Summary/Conclusion: While there is an overall bias between DLA R2-MRI and SDPA R2-MRI, the bias does not result in unacceptable sensitivities and specificities of DLA R2-MRI for predicting SDPA R2-MRI results above the clinically relevant LIC thresholds. However, the bias between the automated and manual methods indicates that the two techniques should not be used interchangeably.
PB2267: COVID-19 OUTCOMES ON HAEMATOLOGY PATIENTS WHO RECEIVED RITUXIMAB: SINGLE CENTRE STUDY
Authors: L. Hariharan, M. Champion-Homfray, E. Hassan
Journal: HemaSphere (2022)

Background: Rituximab is a monoclonal antibody, targeting CD20 on surface of B lymphocytes. It is used in the treatment of various of haematologic conditions. Rituximab treatment is associated with rapid and prolonged B-cell depletion, reduced humoral response and secondary hypogammaglobulinemia. Recovery from which may take up to 12 months, therefore patients who receive rituximab are at increased risk of infectious complications for a long period of time after treatment. Aims: To evaluate the potential impact of prior rituximab therapy on clinical outcomes of COVID-19 infection. Methods: We conducted a retrospective study on haematology patients who received rituximab from December 2019 to October 2021 and were diagnosed with COVID-19 pneumonia. Indications of rituximab were treatment of lymphoma, CLL, and autoimmune haematological disorders. Results: 139 were included in the study. Of these 139 patients, 13 got admitted to the hospital. The reason for hospitalization of patients was severe COVID-19 pneumonia and its complications. Median age was (71.5) years. 5 patients (38.4%) developed severe COVID-19 that ultimately led to their deaths. Mean admission days was (10.5) days. Median time between rituximab and COVID-19 infection was 3.9 months. 5 patients had ITU admissions, 8 had oxygen support, one was discharged on home oxygen. 2 of the patients who died received anti-SARS-CoV-2 monoclonal antibodies which did not seem to improve the condition. Summary/Conclusion: There is no doubt that COVID-19 pandemic presents unprecedented challenge to haematologist and patients receiving rituximab.Our observed mortality in hospitalised patients indicates that a significant proportion of haematology patients recover and survive despite recent rituximab treatment. Further studies including larger cohort of patients are essential to validate that rituximab can be safely delivered for haematology patients. Dose modification regimens, and effects on long term disease control remain to be clarified.
Abstract LB126: Functional limitations in respiratory complex I underlie mitochondrial bioenergetics in human colorectal adenocarcinoma
Authors: Ilya Boykov, McLane M. Montgomery, James T. Hagen, Hannah S. Coalson, Kelsey H. Fisher-Wellman
Journal: Cancer Research (2022)

Abstract Typified by oxidative phosphorylation (OXPHOS), mitochondria catalyze a wide variety of cellular processes now understood to be critical for malignant growth. As such, there is considerable interest in targeting mitochondrial OXPHOS in cancer. The present project was based on the premise that the development of efficacious mitochondrial-targeted anti-cancer compounds requires answering two fundamental questions: 1) is mitochondrial bioenergetics in fact different between cancer and non-cancer cells? and 2) If so, what are the underlying mechanisms? To address these questions, we developed a methodological workflow designed to integrate in vitro functional readouts of mitochondrial flux with mass-spectrometry-based proteomics. This allowed us to directly quantitate both total respiratory capacity and OXPHOS kinetics on a per mitochondrion basis. Experiments were performed in isolated mitochondria prepared from freshly resected human colorectal adenocarcinomas (COAD). Relative to adjacent normal colonic mucosa, tumor mitochondria consistently presented with partial disruptions in respiratory complex I (CI). Surprisingly, CI functional limitations did not impair absolute oxidative flux. Instead, the tumor mitochondrial network displayed clear evidence of intrinsic remodeling. Such remodeling maintained respiratory competence at the expense of decreased oxidative ATP synthesis (i.e., OXPHOS inefficiency or increased ‘uncoupling’). Given recent findings demonstrating that mitochondrial OXPHOS is dispensable for tumor growth, our data raise the intriguing possibility that the requirement for mitochondria in COAD may have little to do with oxidative ATP production, but instead reflect a requirement for accelerated mitochondrial flux to support other aspects of anabolic growth (e.g., extracellular nutrient uptake, NAD+ regeneration, nucleotide synthesis). In this respect, rather than functioning as energy producers, COAD mitochondria may primarily function as ‘energy sinks’. Citation Format: Ilya Boykov, McLane M. Montgomery, James T. Hagen, Hannah S. Coalson, Kelsey H. Fisher-Wellman. Functional limitations in respiratory complex I underlie mitochondrial bioenergetics in human colorectal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB126.
PB1919: S100A9 DEFICIENCY ACCELERATES MDS ASSOCIATED TUMOR ESCAPE VIA PD-1/PD-L1 OVEREXPRESSION
Authors: R. Wang, C. Chang
Journal: HemaSphere (2022)

Background: MDS are mainly characterized by ineffective hematopoiesis contributed to inflammatory signaling or immune dysfunction. Our previous studies have shown that S100a9 expression was higher in low-risk MDS and lower in high-risk MDS. Aims: In recent studies, the tolerable safety profile and positive BM response suggest a beneficial use of anti-PD-1 agents in the treatment of MDS, but the underlying mechanism is still unknown. Methods: In this study, skm-1 cells and k562 cells co-cultured with S100a9 acquired apoptosis features. Moreover, we confirmed the inhibition effect S100a9 on PD-1/PD-L1. Importantly, PD-1/PD-L1 blockade and S100a9 can both activate the PI3K/Akt/mTOR signaling pathway. The cytotoxicity was higher in lower-risk MDS-lymphocytes than in high-risk MDS-lymphocytes, and S100a9 partially rescue the exhausted cytotoxicity in lymphocytes. Results: Our study demonstrated that S100a9 may inhibit MDS associated tumor escape via PD-1/PD-L1 blockade through PI3K/Akt/mTOR signaling pathway activation. Summary/Conclusion: Our findings indicated the possible mechanisms anti-PD-1 agents may contribute to the treatment of MDS. These insights may provide more accurate treatment as the supplementary therapy for MDS patients with high risk mutations, like TP53, N-RAS or other complex mutations.
Abstract 6278: Per- polyfluoroalkyl substance (PFAS) modulates steatosis and fibrogenic signaling in hepatocellular carcinoma cells
Authors: Qi Qi, Suryakant Niture, Sashi Gadi, Deepak Kumar
Journal: Cancer Research (2022)

Abstract Perfluorooctanoic acid (PFOA), heptafluorobutyric acid (HFBA), and perfluorotetradecanoic acid (PFTA) are the per- and polyfluoroalkyl substances (PFAS) and organic pollutants that predominantly exist in the environment. Exposure to PFAS affects immune, thyroid and kidney function, lipid and insulin dysregulation, liver disease, and cancer. Mechanisms underlying the impact of low and physiologically relevant concentration of PFAS in liver diseases remain elusive. In the current study, we investigated the effect of PFOA, HFBA, and PFTA on cell proliferation, steatosis, and fibrogenic signaling in hepatocytes and liver cancer cell models. Exposure of PFOA and PFBA (10 to 1000 nM) specifically promoted cell proliferation in non-tumor derived HepaRG liver cells and in hepatocellular carcinoma HepG2 cells. PFASs increased the expression of TNFα and IL6 inflammatory markers and produced endogenous reactive oxygen species (ROS) production. Further, PFAS enhanced cell steatosis in liver (HepaRG and HepG2) cells which was accompanied by upregulation of steatotic, and fibrogenic markers as well as activated Unfolded Protein Response (UPR) signaling. RNA-seq data suggested that chronic exposures of PFOA modulated the expression of fatty acid/lipid metabolic gene expression that is involved in the development of fatty liver disease. Collectively our data suggests that chronic exposure to low concentration of PFAS may modulate cell steatosis and fibrogenic signaling in hepatocytes and HCC cells by activation of UPR signaling. Citation Format: Qi Qi, Suryakant Niture, Sashi Gadi, Deepak Kumar. Per- polyfluoroalkyl substance (PFAS) modulates steatosis and fibrogenic signaling in hepatocellular carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6278.
P1515: IMPACT OF GENOTYPE ON PANCREATIC IRON OVERLOAD AND IMPAIRED GLUCOSE METABOLISM IN THALASSEMIA MAJOR
Authors: A. Meloni, L. Pistoia, M. Santodirocco, L. Rigoli, C. Bosi, F. M. Pasin, C. Argento, G. Peritore, P. Fina, V. Positano, F. Cademartiri
Journal: HemaSphere (2022)

Background: β-thalassemia major (TM) is characterized by a wide spectrum of clinical manifestations and laboratory findings and the disease phenotype largely depends on the underlying mutations of the β gene. These mutations cause a reduced (β+) or absent (β0) production of the β-globin chain. No study has evaluated the link between genotype and pancreatic iron, representing a powerful predictor for glucose metabolism and cardiac iron and complications. Aims: The objective of this multicenter study was to evaluate the impact of genotype on pancreatic iron levels and glucose metabolism in TM. Methods: We considered 549 TM patients (36.23±10.63 years, 46.3% females), consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. T2* measurements were performed over pancreatic head, body and tail and global value was the mean. The pattern of disturbances of glucose metabolism was assessed by means of the oral glucose tolerance test (OGTT). Results: Three groups of patients were identified: homozygous β+ (N=158), compound heterozygous β0β+ (N=206), and homozygous β0 (N=145). The three groups were homogeneous for age, sex, age at start of regular transfusions and chelation, and frequency of splenectomy. The homozygous β0 group showed significantly lower global pancreas T2* values than the homozygous β+ group (9.91±8.13 ms vs 14.45±10.72 ms; P<0.0001) and the heterozygous β0β+ group (9.91±8.13 ms vs 14.69±10.76 ms; P<0.0001). Pancreatic iron overload (T2*<26 ms) was found in 81.6% of β+β+ patients, 82.5% of β0β+ patients, and 95.1% of β0β0 patients (P<0.0001) (Figure 1A). β0β0 patients were more likely to have pancreatic iron overload than both β+β+ patients (odds ratio-OR=4.39, 95%CI=2.01-9.61; P<0.0001) and β0β+patients (OR=4.14, 95%CI=1.94-8.86; P<0.0001). An altered OGTT was found in 154 patients (34 impaired fasting glucose, 54 impaired glucose tolerance, and 66 diabetes mellitus), all showing pancreatic iron overload. The prevalence of impaired OGTT was significantly higher in the homozygous β0 group than in the homozygous β+ group (34.9 vs 22.4%; P=0.042) (Figure 1B). β0β0 patients had around twice the risk of alterations of glucose metabolism (OR=1.86, 95%CI=1.33-3.07; P=0.014) than β+β+ patients. Image:Summary/Conclusion: In TM the homozygous β0 genotype is associated with higher pancreatic iron levels and prevalence of impaired glucose metabolism. Therefore, the knowledge of the genotype can be useful in the prediction of some phenotypic features and in the clinical and instrumental management of TM patients.
A Smart Near‐Infrared Carbon Dot‐Metal Organic Framework Assemblies for Tumor Microenvironment‐Activated Cancer Imaging and Chemodynamic‐Photothermal Combined Therapy (Adv. Healthcare Mater. 12/2022)
Authors: Yulong Bai, Jingjin Zhao, Liangliang Zhang, Shulong Wang, Jing Hua, Shulin Zhao, Hong Liang
Journal: Advanced Healthcare Materials (2022)

Chemodynamic-Photothermal Therapy In article number 2102759 by Liangliang Zhang, Shulin Zhao, Hong Liang, and co-workers, smart near infrared carbon dot-metal organic framework assemblies are developed for tumor microenvironment (TME)-activated cancer imaging and chemodynamic-photothermal combined therapy.
PB1763: A PHASE 1/2 STUDY TO EVALUATE PONATINIB WITH CHEMOTHERAPY IN PEDIATRIC PATIENTS WITH RELAPSED/RESISTANT/INTOLERANT PHILADELPHIA CHROMOSOME–POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA OR WITH T315I MUTATION
Authors: L. Gore, M. Loh, C.-H. Pui, Y. Matloub, M. J. Hanley, J. Du, M. Hennessy, M. Granier, A. Biondi, L. Silverman
Journal: HemaSphere (2022)

Background: Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) is associated with improved outcomes when tyrosine kinase inhibitors (TKIs) are added to chemotherapy; current 5-year event-free survival (EFS) and overall survival (OS) for newly diagnosed patients (pts) are 60% and 86%, respectively. Ponatinib (PON) is a potent third-generation TKI active against BCR::ABL1 and all identified single resistance mutations, including the gatekeeper T315I mutation that confers resistance to other TKIs. PON is approved for adults with chronic/accelerated/blast-phase chronic myeloid leukemia or Ph+ ALL whose disease is resistant/intolerant to other TKIs or has the T315I mutation. Aims: This study in pediatric pts with relapsed/resistant Ph+ ALL or with the T315I mutation aims to establish the recommended Phase 2 dose (RP2D) of PON and assess the pharmacokinetics, safety, and efficacy of PON in combination with chemotherapy. Methods: This Phase 1/2, single-arm, open-label, multicenter study will enroll pts aged ≥1‒21 years with Ph+ ALL, Ph+ mixed-phenotype acute leukemia, or Ph-like ALL (United States only) who have a targetable kinase-activating lesion and whose disease has relapsed or is resistant/intolerant to ≥1 prior therapy with a BCR::ABL1–targeted TKI or has a BCR::ABL1 T315I mutation. Phase 1 has a rolling 6 design; the first cohort will include up to 12 pts (≥30 kg and able to swallow tablets) for the dose confirmation. Another cohort of 6 pts will be enrolled to assess the age-appropriate mini-tablet formulation at the RP2D. Phase 2 will enroll ≈68 pts, including those enrolled in Phase 1 at the RP2D. Pts aged >16 years must have a Karnofsky performance status of ≥50%; pts aged ≤16 years must have a Lansky Play Scale score of ≥50%. In Phase 1, the primary endpoint is the RP2D of PON in combination with chemotherapy. Secondary endpoints are complete response (CR) rate at the end of the reinduction block and characterization of BCR::ABL1 domain mutations before and after PON treatment. In Phase 2, the primary endpoint is the CR rate at the end of the reinduction block. Secondary endpoints include the proportion of pts in continued CR or who achieve CR at the end of consolidation, EFS, progression-free survival, and OS. Results: The study is currently open and enrolling pts and will include ≈70 study sites in ≈16 countries. Summary/Conclusion: This study will establish the RP2D of PON and assess pharmacokinetics, safety, and efficacy of PON in combination with chemotherapy in pediatric pts with relapsed/resistant Ph+ ALL or with T315I mutation. This abstract is an encore from the Society of Hematologic Oncology 2021 Annual Meeting.
A Facile and Universal Method for Preparing Polyethylene Glycol‐Metal Hybrid Nanoparticles and Their Application in Tumor Theranostics (Adv. Healthcare Mater. 12/2022)
Authors: Zefeng Chen, Yaoxun Zeng, Niping Chen, Mingxia Zhang, Yakun Wang, Zhenxing Pan, Jiongpeng Yuan, Zhaoyi Ye, Xiaojing Li, Wangqing Bian, Haihong Li, Kun Zhang, Yan He, Xujie Liu
Journal: Advanced Healthcare Materials (2022)

Tumor Theranostics In article number 2200044 by Yan He, Xujie Liu, and co-workers, a facile and universal strategy is designed for assembling a range of functional metal ions into 31 types of polyethylene glycol (PEG)-metal hybrid nanoparticles (P-MNPs), which potentially expand the biomedical research of metal ions. As a proof-of-concept, four types P-MNPs containing copper, ruthenium, manganese, and gadolinium ions, respectively, are proven to be tailored for tumor theranostics.